Cigna Medical Coverage Policy

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1 Cigna Medical Coverage Policy Subject Chondrocyte Implantation of the Knee Table of Contents Coverage Policy... 1 General Background... 2 Coding/Billing Information... 8 References... 9 Effective Date... 7/15/2014 Next Review Date... 7/15/2015 Coverage Policy Number Hyperlink to Related Coverage Policies Allograft Transplantation of the Knee Osteochondral Grafts for Articular Cartilage Repair (Autografts, Allografts, and Synthetic Grafts) INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna companies. Coverage Policies are intended to provide guidance in interpreting certain standard Cigna benefit plans. Please note, the terms of a customer s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Proprietary information of Cigna. Copyright 2014 Cigna Coverage Policy Cigna covers autologous chondrocyte implantation as medically necessary for the treatment of a single symptomatic articular cartilage defect of the femoral condyle of the knee (medial, lateral or trochlear) caused by acute or repetitive trauma when ALL of the following criteria are met: age years body mass index (BMI) of < 35 disabling knee pain unresponsive to conservative treatment inadequate response to prior arthroscopic or other surgical repair femoral condyle defect size of 1 10 cm 2 in an area that affects a weight-bearing surface of the femoral condyle, as demonstrated by magnetic resonance imaging (MRI) or arthroscopy articular cartilage defect grade III to IV (full thickness) that involves only cartilage, without associated subchondral bone defect knee is stable with intact, fully functional menisci and ligaments, has normal joint space, and is in good alignment (corrective procedures may be performed in combination with or prior to ACT) patient willing and able to comply with rigorous rehabilitation program no corresponding tibial or patellar lesion ( kissing lesion) with grade III or greater chondromalacia or exposed bone chondromalacia no osteoarthritis of the knee normal articular cartilage at lesion border Cigna does not cover autologous chondrocyte transplantation for any other indication, including but not limited to the following, because it is considered experimental, investigational, or unproven: Page 1 of 12

2 lesions of the tibia or patella lesions in any other joints, including but not limited to the ankle, hip and shoulder treatment of cartilage damage associated with generalized osteoarthritis Cigna does not cover juvenile cartilage allograft tissue implantation (e.g., DeNovo NT Natural Tissue Graft, DeNovo ET Engineered Tissue Graft [ISTO Technologies, Inc., St. Louis, MO / Zimmer, Inc., Warsaw IN]) for the treatment of articular cartilage lesions because it is considered experimental, investigational, or unproven. Cigna does not cover matrix-induced autologous chondrocyte implantation (e.g., MACI Implant [Genzyme Biosurgery, Cambridge, MA]) because it is considered experimental, investigational, or unproven.. General Background Autologous chondrocyte implantation (ACI), also referred to as autologous chondrocyte transplantation (ACT), utilizes a patient s own cells in an effort to repair damage to articular cartilage with the goal of improving joint function and reducing pain. The procedure involves the collection and culture of articular cartilage cells (i.e., chondrocytes) that are then implanted into the cartilage defect with the intent that the cultured cells will contribute to the regeneration and repair of the articular surface. Normal articular cartilage is a complex tissue composed of matrix, chondrocytes and water. The chondrocytes are responsible for synthesizing the matrix, which is composed primarily of collagen fibers, hyaluronate, and sulfated proteoglycans. Cartilage has a poor intrinsic ability to heal itself. When a full-thickness cartilage injury occurs, the articular surface does not usually regenerate on its own. Pain, effusion, and mechanical symptoms are associated with cartilaginous defects. With femoral lesions, pain is usually localized to the medial or lateral tibiofemoral compartment, and is worse with weight bearing or high-impact activity. Lesions of the patella lesions may cause pain with kneeling, stair climbing, and prolonged sitting. The injury often becomes more severe over time since even small defects involving the full thickness of articular cartilage may progress to osteoarthritis, a debilitating joint disease marked by degeneration of the articular cartilage. Nonsurgical treatments for cartilage injury include physical therapy, braces and orthotics, nonsteriodal anti-inflammatory drugs, and intra-articular injection of hyaluronic acid derivatives. Surgical treatment options include arthroscopic lavage and debridement and articular resurfacing techniques. In some patients, total knee replacement may be necessary. The Outer Bridge classification is the most widely used system for judging articular injury to the knee. This system allows delineation of varying areas of chondral pathology, based on the qualitative appearance of the cartilage surface and can assist in identifying those injuries that are suitable for repair techniques. The characterization of cartilage in this system is as follows: grade l, softening with swelling grade ll, fragmentation and fissuring grade lll, fragmentation and fissuring greater than one-half inch in diameter grade lv, subchondral bone exposed Grade lll and lv lesions are thought to be the most suitable for repair techniques. ACI is performed by the harvest of healthy cartilage cells from the patient, preparation and growth of the cells in a culture medium, and implantation of the cultured cells into the articular defect. Healthy cartilage is harvested via biopsy from a minor load-bearing area on a rounded projection of the femur. Cartilage is then minced and washed in a buffered solution and placed in a medium containing digestive enzymes for 15 hours. The cells are then filtered, washed, re-suspended in culture medium containing autologous serum, and seeded in culture flasks. The cells are cultivated for 14 days to six weeks. Ochi et al. (2001) developed a modification of this procedure in which autologous chondrocytes are cultivated in a collagen gel for three weeks. An arthrotomy is performed to inject the cultured cells into the defect. The rate of ACI failure varies, depending on several factors, including defect characteristics, willingness to comply with an intensive rehabilitation regimen, preoperative BMI, and patient age. Obese patients have been shown to have worse knee function prior to ACI and fail to experience sustained benefit following surgery. One comparison of ACI based on patient age demonstrated Page 2 of 12

3 good to excellent results in 83.7% of patients younger than age 20, compared to 55.9% in those older than age 40. Older chondrocytes are thought to have decreased synthetic capabilities and lower response to growth factors. DeNovo NT Natural Tissue Graft (ISTO Technologies, Inc., St. Louis, MO, Zimmer, Inc., Warsaw IN) DeNovo NT Natural Tissue Graft is a juvenile cartilage allograft tissue intended for the repair of articular cartilage defects (e.g., knee, ankle, hip, shoulder, elbow, great toe). The DeNovo NT Graft consists of particulated natural articular cartilage with living cells. Tissues are recovered from juvenile donor joints. The cartilage is manually minced to help with cell migration from the extracellular matrix and facilitate fixation. During implantation, the minced cartilage is mixed in a fibrin glue adhesive. DeNovo NT is classified as minimally manipulated allograft tissue and is therefore not subject to the FDA premarket approval process. A case series evaluating this product for the treatment of articular cartilage defects of the knee began in 2006 and is expected to be completed in There are no studies evaluating the DeNovo NT Natural Tissue Graft in the published medical literature. Matrix-Induced Autologous Chondrocyte Implantation (MACI Implant [Genzyme Biosurgery, Cambridge, MA]): MACI is a procedure in which cartilage cells are removed during arthroscopy, and shipped to a laboratory, where the cells are cultured over a period of several weeks. The cells are seeded on a membrane, and once the culturing process is complete, the cells seeded on the membrane are returned to the surgeon for implantation during a second procedure. The membrane is placed into the defect, and over several months the cells create a matrix that is intended to cover the articular surface of the knee. MACI has been used in Europe but is not available in the United States (Genzyme website, 2012). U.S. Food and Drug Administration (FDA) The FDA determined that Carticel (Genzyme Corporation, Cambridge, MA), a commercial process of producing autologous chondrocytes for transplantation, fell outside existing regulations regarding medical technology. The FDA permitted marketing of the service while guidelines were developed for manipulated autologous structural cells. In May 1996, the FDA announced its guidelines for manipulated autologous structures, which include completion of a Biologics Licensing Application (BLA) and evidence of product safety and efficacy. On August 22, 1997, the FDA granted a Biologics License for Carticel, for provision of autologous chondrocytes for the repair of clinically significant, symptomatic cartilaginous defects of the femoral condyle caused by acute or repetitive trauma. The FDA based its approval of Carticel primarily on a number of case reports consisting of 153 patients treated in Sweden, and early data from a US registry of patients treated with Carticel. As a condition of approval, the FDA requested that Genzyme conduct two randomized controlled studies one to determine the contribution of the cartilage cells to the treatment of the defect, and the other to compare longterm outcomes in patients treated with Carticel to outcomes achieved with other procedures currently in use, including abrasion arthroplasty and microfracture. In addition, all patients enrolled in the Carticel Patient Registry must be followed for a minimum of two years with submission of periodic reports of safety and clinical outcomes to the FDA. Genzyme subsequently concluded that running randomized trials sufficiently large enough to satisfy these requirements would not be feasible and requested that the FDA narrow the indication for autologous cultured chondrocytes to second-line therapy for patients who have failed other therapies. The FDA granted a supplement to the Biologics License for Carticel on March 2, In response to the request made by Genzyme. FDA narrowed the indication for use of autologous cultured chondrocytes to second-line therapy for patients who have failed other therapies. In June 2007, the FDA granted a request from Genzyme to supplement the biologics license application for Cultured Chondrocytes to revise the package insert to include safety and efficacy data from the Study of the Treatment of Articular Repair (STAR), discussed below. The STAR study fulfilled the post-approval commitment to conduct a prospective, longitudinal, multicenter study of 100 subjects with articular cartilage defects of the medial or lateral condyles or trochlea having inadequate response to prior non-carticel surgical treatment (including marrow stimulation techniques, transplantation of cells or tissues, or debridement followed by an adequate rehab program, but not including lavage, biopsy, or diagnostic arthroscopy). The June 2007 package insert contains the following indications and usage information: Carticel is an autologous cellular product indicated for the repair of symptomatic cartilage defects of the femoral condyle (medial, lateral or trochlea), caused by acute or repetitive trauma, in patients who have Page 3 of 12

4 had an inadequate response to a prior arthroscopic or other surgical repair procedure (e.g., debridement, microfracture, drilling/abrasion arthroplasty, or osteochondral allograft/autograft). Carticel should only be used in conjunction with debridement, placement of a periosteal flap and rehabilitation. Carticel is not indicated for: Treatment of cartilage damage associated with generalized osteoarthritis Patients with total mensicectomy, unless surgically reconstructed prior to or concurrent with Carticel implantation The 2007 package insert listed the following as the most common serious adverse events (> 5% of patients) from the STAR study: arthrofibrosis/joint adhesions, graft overgrowth, chondromalacia or chondrosis, cartilage injury, graft complication, meniscal lesion and graft delamination. Literature Review Niemeyer et al. (2013) published a case series evaluating long-term clinical and MRI outcomes of ACI of the knee (n=86). Defects were located on the medial femoral condyle in 34 patients, lateral femoral condyle in 13, trochlear groove in 6, and patellar lesions in 17 patients. The mean age of treated patients was 33, and the mean BMI, At a mean follow-up of 10.9 ± 1.1 years, 70 patients were available for evaluation of knee function using standard instruments, and 59 of these patients were evaluated by MRI to quantify the MR observation of cartilage repair tissue (MOCART) score. Clinical function was assessed using the Lysholm score, International Knee Documentation Committee (IKDC) score, and the Knee Injury and Osteoarthritis Outcome Score (KOOS). Patient activity was assessed using the Tegner score, and pain was assessed using a visual analog scale (VAS). The mean IKDC score at follow-up was 74.0 ± The mean Lysolm score improved from 42.0 ± 22.5 before surgery to 71.0 ± 17.4 at follow-up (p<.01). The mean pain score decreased from 7.2 ± 1.9 to 2.1 ± 2.1. The mean MOCART score was 44.9 ± Defect-associated bone marrow edema was found in 78% of cases. There was no correlation between MOCART score and clinical outcome (KDC score). The authors concluded that although ACI leads to satisfying clinical results in terms of patient satisfaction, pain reduction, and improvement in knee function, full restoration of knee function cannot be achieved. Bentley et al. (2012) conducted a randomized comparative study of autologous chondrocyte implantation (ACI) vs. mosaicplasty for symptomatic articular cartilage lesions of the knee (n=100). Patients with an isolated articular cartilage lesion with persistent knee pain and functional deficit in a stable knee were randomized to undergo ACI (n= 58) or mosaicplasty (n=42). Lesions were located on the medial femoral condyle (53), lateral femoral condyle (18) or patella (25). The rehabilitation protocol was identical in both groups. Assessment was performed using the modified Cincinnati knee score and the Stanmore-Bentley Functional Rating system. At ten years, 10 of 58 (17%) patients in the ACI group experienced repair failure compared to 23 of 42 (55%) in the mosaicplasty group (p<0.001). Of those with a surviving graft, the functional outcome was significantly better in patients who underwent ACI compared to mosaicplasty (p=0.02). Harris et al. (2010) conducted a systematic review to determine a) whether the current literature supports the choice of using autologous chondrocyte implantation (ACI) over other cartilage procedures, b) whether the literature supports the use of a specific generation of ACI, and c) whether there are patient-specific and defectspecific factors that influence outcomes. Thirteen randomized controlled and prospective cohort studies (917 patients) met the inclusion criteria. Patients underwent ACI (n=604), microfracture (n=271), or osteochondral autograft (n=42). Improvement was seen with all surgical techniques compared to preoperative status. Three of seven studies showed better clinical outcomes after ACI compared to microfracture after one to three years of follow-up; one study showed better outcomes two years after microfracture, and three studies showed no difference in these treatments after one to five years. Clinical outcomes after microfracture deteriorated at months in three of seven studies. ACI and osteochondral autograft demonstrated equivalent short-term clinical outcomes, but improvement was more rapid following osteochondral autograft. Outcomes were similar between first and second generation ACI, and between open and arthroscopic ACI, but complication rates were higher with open, periosteal-cover, first-generation ACI (four studies). For both ACI and microfracture, the best outcomes were seen in younger patients with a shorter preoperative duration of symptoms. A defect size of > 4 cm 2 was the only predictor of better outcomes when ACI was compared with a non-autologous chondrocyte implantation technique. Page 4 of 12

5 A Cochrane systematic review of autologous chondrocyte implantation (ACI) for full thickness articular cartilage defects of the knee (Vasiliadis and Wasiak, updated 2010, included six trials with 431 patients. Methodological flaws of the trials included incomplete follow-up and inadequate outcomes reporting. Three of the trials compared ACI vs. mosaicplasty; one reported statistically significant results in favor of ACI at one year, based on the number of patients with good or excellent functional results. A second trial found significant improvement in the mosaicplasty group when assessed using one functional scoring system at two years, but no differences based on two other scoring systems. A third trial found no difference between ACI and mosaicplasty at an average of ten months after surgery. In trials comparing ACI with microfracture, there was no statistically significant difference in functional outcomes at two years. Results of the sixth trial comparing matrixguided ACI vs. microfracture were undetermined due to significant loss to follow-up. The authors concluded that there is insufficient evidence to draw conclusions on the use of ACI for treating full thickness articular cartilage defects in the knee. Further good quality randomized controlled trials with long-term functional outcomes are required. The Study of the Treatment of Articular Repair (STAR) (Zaslav et al., 2009), a prospective, longitudinal, multicenter study, examined the efficacy, durability and safety of ACI in patients with failed prior treatment for articular cartilage defects of the knee (n=154). Eligibility criteria included a history of at least one grade III or IV defect located on the medial or lateral femoral condyle or trochlea, and an inadequate response to a prior non- ACI surgical procedure performed within three years to treat the cartilage lesion. Patients with any of the following were excluded: previous ACI treatment on the ipsilateral knee; history of total meniscectomy or required concurrent total meniscectomy; grade III or IV defects on areas other than the medial or lateral femoral condyle or the trochlea; or widespread osteoarthritis or inflammatory arthritis of the involved knee. Of 154 patients who received ACI, 126 (82%) completed the protocol. Mean follow-up was 45.3 months; median followup was 48.7 months. The treatment was considered successful in 76% of patients, and 24% were considered treatment failures. Mean improvements were seen from baseline to all time points (p<.001) for all outcome measures. Preoperative and 48 month results, respectively, were 48.7 and 72.2 on the Knee Injury and Osteoarthritis Outcome Score subscales of pain; 51.8 and 70.8 for other symptoms, 29.0 and 52.2 for knee quality of life, and 58.6 and 81.0 for ADL. Preoperatively and at 48 months, respectively, Modified Cincinnati Overall Knee scores were 3.3 and 6.3; Visual Analog Scores were 28.8 and 69.9, and SF-36 Overall Physical Health scores were 33.0 and The most frequent serious adverse events were graft overgrowth, arthrofibrosis, cartilage injury, chondromalacia, graft complication, and meniscus lesion. A total of 84 patients (54%) experienced at least one serious adverse event. A total of 76 patients (49%) underwent a total of 113 subsequent surgical procedures, primarily arthroscopy or manipulation under anesthesia, during the four year follow-up. The authors noted that the subsequent surgical procedure rate in this study appears higher than generally reported after ACI. Knutsen et al. (2007) published five-year results of a randomized controlled trial that compared ACI to microfracture in 80 patients with a single symptomatic cartilage defect on the femoral condyle in a stable knee. The procedure was considered to have failed if the patient required reoperation because of symptoms due to a lack of healing of the treated defect. At five years, there were nine failures (23%) in each group, compared to the two year results of two failures in the ACI group and one failure in the microfracture group. Seven patients were unavailable for examination. Failure occurred at a mean of 26.2 months after ACI and 37.8 months after microfracture treatment (p=0.101). In the patients who did not have a failure, the mean Lysholm scores and mean pain scores on the visual analog scale (VAS) remained significantly improved (p<0.05). When adjustments were made for pretreatment measurements using linear regression analysis, there was no significant difference between the two treatment groups at five years in the Lysholm score (p=0.227) or VAS (p=0.278). There was no significant improvement from baseline in the SF-36 physical component score in the ACI group (p=0.309). There was a significant improvement in the microfracture group, however (p<0.001). Patients less than age 30 had a better outcome, regardless of the treatment group. The authors proposed that, based on these results, microfracture, a less costly, less invasive procedure, should be preferred as the first-line cartilage repair procedure for defects located on the medial or lateral femoral condyle of the knee. The authors stated that ACI may be preferred as a second-line treatment, particularly for large defects that are not contained. Mandelbaum et al. (2007) conducted a case series to test the hypothesis that patients treated with ACI for moderate to large isolated lesions located on the trochlea will report improvement in the modified overall condition scale score of the Cincinnati Knee Rating System. This rating system assigns a score from one (poor) to ten (excellent). Patients from the Cartilage Repair Registry (n=40) rated their overall condition and symptoms at baseline, and at a mean follow-up of 59 ± 18 months. Patients were age 16 48, and had a mean total defect Page 5 of 12

6 size of 4.5 cm 2. Many patients (48%) had failed a prior marrow stimulation procedure. Tibiofemoral osteotomy had been performed in 23% of patients at baseline, and lateral release or Fulkerson for patella maltracking had been performed on 13% of patients. The mean BMI of included patients was 27.2 and mean age, 37 years (range 16-48). Patients reported a mean improvement in their overall condition score from 3.1 ± 1.0 points at baseline, to 6.4 ± 1.7 points at follow-up (p<.0001). Pain and swelling scores also improved from 2.6 ± 1.7 to 6.2 ± 2.4 points, and 3.9 ± 2.7 to 6.3 ± 2.7 points, respectively (p<.0001). The degree of improvement was not significantly different between patients who had a concurrent procedure with ACI and those who did not. There were no failed implantations. Eleven patients received subsequent procedures for adhesions, periosteal flap detachment, chondromalacia, loose bodies, torn meniscus, fibrotic tissue, and decreased range of motion. Wood et al. (2006) reported on an investigation performed at the FDA Center for Biologics Evaluations and Research that describes the adverse events following Carticel implantation as reported to the FDA from 1996 to FDA regulations require manufacturers to report adverse events. Since reporting by clinicians and others is voluntary, adverse event reporting is likely to underestimate the number of event occurrences. A total of 497 adverse events among 294 patients receiving Carticel were reported. Of the 270 events for which the anatomic site was noted, 258 (96%) involved the femoral condyles. More than one adverse event was reported for 135 patients (46%). The most commonly reported events were graft failure (n=73; 25%), delamination (n= 65; 22%), and tissue hypertrophy (n= 52; 18%). Eighteen surgical site infections were reported, including 11 joint and seven soft-tissue infections. Surgical revision subsequent to Carticel implantation was mentioned in the records for 273 patients (93%). The reasons for the 389 revision procedures included graft-related problems (187 procedures; 48.1%), periarticular soft-tissue problems (97 procedures; 24.9%), and intra-articular problems (63 procedures; 16.2%). Eight patients had a total knee replacement. Based on the manufacturer s reported distribution of 7500 Carticel lots between 1995 and 2002, 285 patients (3.8%) had an adverse event that was reported to the FDA. Brown et al. (2005) conducted a multicenter cohort study to assess the clinical outcome of patients treated with ACI for lesions of the distal femur. Modified 10-point scales of the Cincinnati knee rating system were used to measure outcome assessments at baseline and at five years. Eighty-seven percent of patients completed fiveyear follow-up assessments. Patients were an average of age 37 and had a mean total defect size of 4.9 cm 2. At least one prior cartilage repair procedure had failed in 70% of the patients. At follow-up, 87 patients reported a mean improvement of 2.6 points in the overall condition score, including 62 with improved conditions, six with no change in condition, and 19 with worsened conditions. The authors stated that the factors that contributed to some treatment failures highlight the importance of careful clinical evaluation and patient selection. Ligament instability and joint malalignment should be corrected either before or concurrent with ACI. The authors also stated that ACI is not indicated for cartilage damage associated with osteoarthritis or inflammatory arthritis. Of the 62 patients who improved, the mean overall condition score improved 4.1 points at follow-up. Horas et al. (2003) conducted a randomized controlled trial to investigate two-year outcomes in 40 patients with an articular cartilage lesion of the femoral condyle who had been randomly treated with either transplantation of an autologous osteochondral cylinder or ACI. Biopsy specimens from representative patients of both groups were evaluated with histological staining, immunochemistry, and scanning electron microscopy. Both surgical treatments resulted in a decrease in symptoms, although the improvement provided by ACI lagged behind that provided by the osteochondral cylinder transplantation. The authors report that the defects treated with ACI were primarily filled with fibrocartilage, whereas the osteochondral cylinder transplants retained their hyaline character (e.g., a more favorable outcome), although there was a persistent interface between the transplant and the surrounding original cartilage. Limitations to this study included the small number of patients and limited follow-up of two years. Jobanputra et al. (2001) conducted a systematic review commissioned by the UK National Health Service on behalf of the National Institute for Clinical Excellence (NICE). Seventeen studies (n=2600 patients) who were treated with ACT were reviewed. All reports included in the analysis were case series with variable follow-up times. The outcome of the surgery two years after treatment was rated as good or excellent by 70% of the patients. Approximately 16% of the patients required further arthroscopic surgical procedures during follow-up, and treatment was judged to have failed in 3 7% of the patients. The two-year outcome for comparator treatments was rated as good or excellent in 10 95% of patients. The authors concluded that the literature on ACT and comparators is subject to bias because of the inherent weaknesses of case series, and stated that the long-term impact of conventional surgical treatments or no surgical treatment is poorly documented. Recommendations for further research included the need to provide more accurate data on the occurrence of Page 6 of 12

7 hyaline cartilage defects, evaluate the natural history of cartilage defects, clarify the relationship of cartilage defects to clinical symptoms, and compare ACT with other treatments based on randomized trials. The use of ACI became widely available in the U.S. following FDA approval of Carticel and early reports of success in Sweden, although controversy remains regarding the efficacy of the procedure and indications for use. The Washington State Department of Labor and Industries guideline, Review Criteria for Knee Surgery, (2004, updated 2012) includes the following findings for consideration of ACI. physical therapy for a minimum of two months capable and willing to follow the rehabilitation protocol failure of traditional surgical interventions (i.e., microfracture, drilling, abrasion, osteochondral graft) Debridement alone does not constitute a traditional surgical intervention for ACI. single, clinically significant lesion that measures between 1 10 cm 2 in area that affects a weight-bearing surface of the medial femoral condyle or the lateral femoral condyle full-thickness lesion (Modified Outerbridge Grade III IV) that involves only cartilage knee is stable with intact, fully functional menisci and ligaments normal knee alignment normal joint space less than 60 years old body mass index (BMI) of less than 35 Chondral defect on the weight bearing surface of the medial or lateral femoral condyle on: MRI or arthroscopy The guideline lists the following exclusion criteria for ACI: lesion that involves any portion of the patellofemoral articular cartilage, bone, or is due to osteochondritis dissecans a "kissing lesion" or *Modified Outerbridge Grade II, III, or IV exists on the opposite tibial surface mild to severe localized or diffuse arthritic condition that appears on standing x-ray as joint space narrowing, osteophytes, or changes in the underlying bone unhealthy cartilage border; the synovial membrane in the joint may be used as a substitute border for up to 1/4 of the total circumference prior total meniscectomy of either compartment in the affected knee. Must have at least 1/3 of the posterior meniscal rim history of anaphylaxis to gentamycin or sensitivity to materials of bovine origin chondrocalcinosis diagnosed during the cell culture process Matrix-Induced Autologous Chondrocyte Implantation (MACI Implant : A prospective case series was conducted by Ebert et al. (2011) to assess clinical and MRI-based outcomes to five years in 41 patients (53 grafts) after MACI. Following surgery and a 12-week structured rehabilitation program, patients underwent clinical assessments (Knee injury and Osteoarthritis Outcomes Score, SF-36, 6-minute walk test, knee range of motion) and MRI assessments at 3, 12, 24 months, and 5 years after surgery. A significant improvement was demonstrated for all Knee Injury and Osteoarthritic Outcome Scores and SF-36 subscales, as well as the 6- minute walk test and active knee extension (p<0.05). At five years, 67% of MACI grafts demonstrated complete infill, while 89% demonstrated good to excellent filling of the chondral defect. The authors concluded that these results suggest that MACI provides a suitable midterm treatment option for articular cartilage defects in the knee. Long term follow-up is essential to confirm whether the repair tissue has the durability required to maintain long-term patient quality of life. Zeifang et al. (2010) conducted a randomized controlled trial to compare MACI vs. the original periosteal flap technique (n=21). At one and two-year follow-up, no difference in efficacy was reported in knee function as assessed by the International Knee Documentation Committee (IKCD), and no difference was reported in the health-related quality of life (Short Form-36) and knee functionality (Tegner Activity Score). Significant differences in knee functionality (Lysholm and Gilquist score) were found in favor of the periosteal flap technique. Page 7 of 12

8 Basad et al. (2010) conducted a randomized controlled trail to compare clinical outcomes of patients with symptomatic cartilage defects treated with MACI (n=40) or microfracture (n=20). Outcome measures included the Tegner, Lysholm and International Cartilage Repair Society (ICRS) scores. The difference between baseline and 24 months was significant for both treatment groups for the Tegner, Lysolm patient ICRS, and surgeon ICRS scores (all p<0.0001), but MACI was more effective than microfracture according to the Lysolm (p=0.0005), Tegner (p=0.04), ICRS patient (p=0.03) and ICRS surgeon (p=0.02) scores. There is insufficient evidence in the published medical literature to demonstrate the safety and efficacy of matrix-induced autologous chondrocyte transplantation (MACI), or to determine how this technique compares to the standard periosteal flap technique. ECRI An ECRI Institute Evidence Report, Autologous Chondrocyte Implantation for Knee Cartilage Defects (ECRI, 2004) concluded that there is insufficient evidence to determine whether ACI is effective for treating cartilage defects of the knee. The three available controlled trials compared ACI to competing technologies (e.g., mosaicplasty, microfracture). These trials did not provide the most appropriate control group to determine ACI s basic efficacy. Because hyaline cartilage regenerates over a long period of time, the controlled trials that followed patients for one year and two years do not provide the long-term evidence needed to reach conclusions about the efficacy of the ACI techniques. The report states that, thus far, ACI has not produced durable hyaline cartilage in most patients, and that was the rationale behind the technology s initial development. Adverse event rates cannot be reliably calculated from the small studies that reported such occurrences. Use Outside the U.S. National Institute for Clinical Excellence (NICE) (United Kingdom) Guidance issued in 2005 states that autologous chondrocyte implantation (ACI) is not recommended for the treatment of articular cartilage defects of the knee joint except in the context of ongoing or new clinical studies that are designed to generate robust and relevant outcome data, including the measurement of health-related quality of life and long-term follow-up. Patients should be fully informed of the uncertainties about the long-term effectiveness and the potential adverse effects of this procedure. Summary Prospective, randomized clinical studies are needed to assess the impact of autologous chondrocyte transplantation (ACT) on functional status, disability, and pain. In addition, studies need to compare the effectiveness of ACT to established methods of treatment of cartilage defects of the knee. Based on the available evidence, guidelines, and revised FDA indications for use, ACT should be limited to use as a secondline treatment for carefully selected symptomatic individuals with defects of the femoral condyle caused by acute or repetitive trauma who have had an inadequate response to prior arthroscopic or other surgical repair. The DeNovo NT Natural Tissue Graft, a minced juvenile cartilage allograft has been proposed for the treatment of articular cartilage lesions. There are no studies evaluating these products in the published medical literature. There is insufficient evidence to determine the safety and efficacy of this procedure n the treatment of articular cartilage defects of the knee. There is insufficient evidence in the published medical literature to demonstrate the safety and efficacy of matrix-induced autologous chondrocyte transplantation (MACI Implant [Genzyme Biosurgery, Cambridge, MA]), or to determine how this technique compares to the standard periosteal flap technique. Coding/Billing Information Note: 1) This list of codes may not be all-inclusive. 2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement Covered when medically necessary for autologous chondrocyte implantation (excludes juvenile cartilage allograft tissue implantation and matrix-induced autologous chondrocyte implantation which are experimental/investigation/unproven and not covered for any indication): Page 8 of 12

9 CPT * Description Codes Autologous chondrocyte implantation, knee HCPCS Codes J7330 S2112 Description Autologous cultured chondrocytes, implant Arthroscopy, knee, surgical harvesting of cartilage (chondrocyte cells) Experimental/Investigational/Unproven/Not Covered when used to report juvenile cartilage allograft tissue implantation or matrix-induced autologous chondrocyte implantation: CPT* Codes Description Unlisted procedure, femur or knee *Current Procedural Terminology (CPT ) 2013 American Medical Association: Chicago, IL. References 1. Alleyne K, Galloway MT. Osteochondral injuries of the knee. Clin Sports Med 2001;20(2) Basad E, Ishaque B, Bachmann G, Stürz H, Steinmeyer J. Matrix-induced autologous chondrocyte implantation versus microfracture in the treatment of cartilage defects of the knee: a 2-year randomised study. Knee Surg Sports Traumatol Arthrosc Apr;18(4): Bentley G, Biant LC, Vijayan S, Macmull S, Skinner JA, Carrington RW. Minimum ten-year results of a prospective randomised study of autologous chondrocyte implantation versus mosaicplasty for symptomatic articular cartilage lesions of the knee. J Bone Joint Surg Br Apr;94(4): doi: / X.94B Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med Oct;331(4): Brittberg M, Tallheden T, Sjögren-Jansson E. Autologous chondrocytes used for articular cartilage repair: an update. Clin Orthop. 2001;391(s):S Brittberg M, Winalski CS. Evaluation of cartilage injuries and repair. J Bone Joint Surg Am. 2003;85-A Suppl 2: Browne J, Anderson A, Arciero R, Mandelbaum B, Moseley J, Micheli L, et al. Clinical Outcome of Autologous Chondrocyte Implantation at 5 Years in US Subjects. Clin Orthop Relat Res 2005 Jul;(436): Canale & Beaty: Campbell s operative orthopaedics, 12th ed. Mosby: an imprint of Elsevier; Clinical Trials.gov. Post market study of DeNovo NT, Natural Tissue Graft. Accessed Apr 30, Available at URL address: Easley ME, Scranton PE. Osteochondral autologous transfer system. Foot Ankle Clin Jun;8(2): Ebert JR, Robertson WB, Woodhouse J, Fallon M, Zheng MH, Ackland T, Wood DJ. Clinical and magnetic resonance imaging-based outcomes to 5 years after matrix-induced autologous chondrocyte Page 9 of 12

10 implantation to address articular cartilage defects in the knee. Am J Sports Med Apr;39(4): Epub 2011 Jan ECRI Institute. Hotline Response [database online]. Plymouth Meeting (PA): ECRI Institute. Carticel Autologous Cultured Chondrocytes (Genzyme Biosurgery Corp.) Implantation for Repairing Articular Cartilage Knee Injuries Mar. Available at URL address: ECRI Institute. Autologous Chondrocyte Implantation for Knee Cartilage Defects. Plymouth Meeting (PA): ECRI Institute Technology Assessment Information Service: 2004 July1. Available at URL address: ECRI Institute. Hotline Response [database online]. Plymouth Meeting (PA): ECRI Institute. DeNovo NT Natural Tissue Graft (Zimmer, Inc.) for Repairing Cartilage 2013 Aug Available at URL address: Filardo G, Kon E, Andriolo L, Di Martino A, Zaffagnini S, Marcacci M. Treatment of "patellofemoral" cartilage lesions with matrix-assisted autologous chondrocyte transplantation: a comparison of patellar and trochlear lesions. Am J Sports Med Mar;42(3): doi: / Epub 2013 Dec Genzyme Corporation. Carticel autologous cultured chondrocytes. Accessed May 16, Available at URL address: Giannini S, Buda R, Grigolo B, Vannini F. Autologous chondrocyte transplantation in osteochondral lesions of the ankle joint. Foot & ankle 2001;22(6): Gillogly SD, Arnold RM. Autologous chondrocyte implantation and anteromedialization for isolated patellar articular cartilage lesions: 5- to 11-year follow-up. Am J Sports Med Apr;42(4): doi: / Epub 2014 Feb Gillogly SD, Myers TH. Treatment of full-thickness chondral defects in the knee with autologous chondrocyte implantation. J Orthop Sports Phys Ther Oct;36(10): Harris JD, Siston RA, Pan X, Flanigan DC. Autologous chondrocyte implantation: a systematic review. J Bone Joint Surg Am Sep 15;92(12): Henderson IJ, Tuy B, Connell D, Oakes B, Hettwer WH. Prospective clinical study of autologous chondrocyte implantation and correlation with MRI at three and 12 months. Bone Joint Surg Br Sep;85(7): Horas U, Pelinkovic D, Herr G, Aigner T, Schnettler R. Autologous chondrocyte implantation and osteochondral cylinder transplantation in cartilage repair of the knee joint. A prospective, comparative trial. J Bone Joint Surg Am Feb;85-A(2): Jobanputra O, Parry D, Fry-Smith A, Burls A. Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review. Health Technol Assess 2001 May;5(11): Koopman W, Moreland, L. Editors. Arthritis & Allied Conditions Lippincott Williams & Wilkins, Knutsen G, Drogset JO, Engebretsen L, Grontvedt T, Isaksen V, Ludvigsen TC, et al. A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am Oct;89(10): Knutsen G, Engebretsen L, Ludvigsen T, Drosgset J, Grontvedt T, Solheim E, et al. Autologous chondrocyte implantation compared with microfracture in the knee. J Bone & Joint Surg March;86-A(3): Page 10 of 12

11 27. Mandelbaum B, Browwne JE, Fu F, Micheli LJ, Moseley Jr JB, Erggelet C, Anderson AF. Treatment outcomes of autologous chondrocyte implantation for full-thickness articular cartilage defects of the trochlea. Am J Sports Med Jun;35(6): Epub 2007 Mar McCormick F, Yanke A, Provencher MT, Cole BJ. Minced articular cartilage--basic science, surgical technique, and clinical application. Sports Med Arthrosc Dec;16(4): McNickle AG, Provencher MT, Cole BJ. Overview of existing cartilage repair technology. Sports Med Arthrosc Dec;16(4): Minas T, Peterson L. Complex topics in knee surgery. Advanced techniques in autologous chondrocyte transplantation Surgical management of isolated chondral defects. Clin Sports Med 1999 Jan;18(1): Moseley J, O'Malley K, Petersen N, Menke T, Brody B, Kuykendall D, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 2002; 347: National Institute for Clinical Excellence (NICE). Technology appraisal guidance 89. The use of autologous chondrocyte implantation for the treatment of cartilage defects in knee joints. London, UK: NICE; 2005 May. Accessed May 16, Available at URL address: Niemeyer P, Porichis S, Steinwachs M, Erggelet C, Kreuz PC, Schmal H, et al. Long-term outcomes after first-generation autologous chondrocyte implantation for cartilage defects of the knee. Am J Sports Med Jan;42(1): doi: / Epub 2013 Oct Ossendorf C, Kaps C, Kreuz C, Burmester GR, Sittinger M, Erggelet C. Treatment of posttraumatic and focal osteoarthritic cartilage defects of the knee with autologous polymer-based three-dimensional chondrocyte grafts: 2-year clinical results. Arthritis Res Ther. 2007;9(2):R Peterson L, Minas T, Brittberg M, Lindahl A. Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation; results at two to ten years. Clin Orthop. 2000;374(5): Scopp JM, Mandelbaum BR. A treatment algorithm for the management of articular cartilage defects. Orthop Clin North Am Oct;36(4): U.S. Food and Drug Administration (FDA). Center for biologics evaluation and research. Accessed May 16, Carticel. Available at URL address: 25.htm 38. Vasiliadis HS, Wasiak J. Autologous chondrocyte implantation for full thickness articular cartilage defects of the knee. Cochrane Database Syst Rev Oct 6;(10):CD Visna P, Adler J, Pasa L, Kocis J, Cizmar I, Horky D. Autologous chondrocyte transplantation for the treatment of articular defects of the knee. Scr Med 2003 June;76(3): Washington State Department of Labor and Industries. Review criteria for knee surgery. Released 1991, updated Oct Provider Bulletin 2003 Dec(PB-03-06):1-7. Accessed May 16, Available at URL address: Wood J, Malek M, Frassica F, Polder J Mohan A, Bloom E, et al. Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration. J Bone Joint Surg 2006 Mar;88(3): Zaslav K, Cole B, Brewster R, DeBerardino T, Farr J, Fowler P, Nissen C; STAR Study Principal Investigators. A prospective study of autologous chondrocyte implantation in patients with failed prior Page 11 of 12

12 treatment for articular cartilage defect of the knee: results of the Study of the Treatment of Articular Repair (STAR) clinical trial. Am J Sports Med Jan;37(1): Epub 2008 Oct Zeifang F, Oberle D, Nierhoff C, Richter W, Moradi B, Schmitt H. Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial. Am J Sports Med May;38(5): Epub 2009 Dec Zimmer, Inc. DeNovo NT Natural Tissue Graft. Accessed May 16, Available at URL address: The registered marks "Cigna" and the "Tree of Life" logo are owned by Cigna Intellectual Property, Inc., licensed for use by Cigna Corporation and its operating subsidiaries. All products and services are provided by or through such operating subsidiaries and not by Cigna Corporation. Such operating subsidiaries include Connecticut General Life Insurance Company, Cigna Health and Life Insurance Company, Cigna Behavioral Health, Inc., Cigna Health Management, Inc., and HMO or service company subsidiaries of Cigna Health Corporation. Page 12 of 12